Six2 and Wnt Regulate Self-Renewal and Commitment of Nephron Progenitors through Shared Gene Regulatory Networks

A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates mammalian nephrogenesis. Intersectional studies using chromatin immunoprecipitation and transcriptional profiling identified direct target genes shared by each pathway within nephron progenitors. Wnt4 and Fgf8 are essential for progenitor commitment; cis-regulatory modules flanking each gene are co-bound by Six2 and β-catenin, and dependent on conserved Lef/Tcf binding sites for activity. In vitro and in vivo analyses suggest that Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance while entry of β-catenin into this complex promotes nephrogenesis. Alternative transcriptional responses associated with Six2 and β-catenin co-binding events occur through non-Lef/Tcf DNA binding mechanisms highlighting the regulatory complexity downstream of Wnt signaling in the developing mammalian kidney

Management of chronic kidney disease–mineral and bone disorder: Korean working group recommendations

For Korean dialysis patients, chronic kidney disease–mineral bone disorder is a serious burden because of cardiovascular calcification and mortality. However, recent epidemiologic data have demonstrated that many patients undergoing maintenance hemodialysis are out of the target ranges of serum calcium, phosphorus, and intact parathyroid hormone. Thus, we felt the necessity for the development of practical recommendations to treat abnormal serum phosphorus, calcium, and iPTH in dialysis patients. In this paper, we briefly comment on the measurement of serum calcium, phosphorus, iPTH, dialysate calcium concentration, dietary phosphorus restriction, use of phosphate binders, and medical and surgical options to correct secondary hyperparathyroidism. In particular, for the optimal management of secondary hyperparathyroidism, we suggest a simplified medication adjustment according to certain ranges of serum phosphorus and calcium. Large-scale, well-designed clinical studies are required to support our strategies to control chronic kidney disease–mineral bone disorder in this country. Based on such data, our practice guidelines could be established and better long-term outcomes should be anticipated in our dialysis patients

Multi-Objective Land-Use Allocation Considering Landslide Risk under Climate Change: Case Study in Pyeongchang-gun, Korea

Extreme landslides triggered by rainfall in hilly regions frequently lead to serious damage, including casualties and property loss. The frequency of landslide occurrences may increase under climate change, due to the increasing variability of precipitation. Developing urban areas outside landslide risk zones is the most effective method of reducing or preventing damage; however, planning in real life is a complex and nonlinear problem. For such multi-objective problems, genetic algorithms may be the most appropriate optimization tools. Therefore, in this study, we suggest a comprehensive land-use allocation plan using the Non-dominated Sorting Genetic Algorithm II to overcome multi-objective problems, including the minimization of landslide risk, minimization of change, and maximization of compactness. Our study area is Pyeongchang-gun, the host city of the 2018 Winter Olympics in Korea, where high development pressure has resulted in urban sprawl into the hazard zone where a large-scale landslide occurred in 2006. We obtain 100 Pareto plans that are better than the actual land use data for at least one objective, with five plans that explain the trade-offs between meeting the first and second objectives. The results can be used by decision makers for better urban planning and for climate change-related spatial adaptation

Paclitaxel–Nanodiamond Nanocomplexes Enhance Aqueous Dispersibility and Drug Retention in Cells

Nanodiamonds (NDs) with 5 nm crystalline structures have been recognized as emerging carbon delivery vehicles due to their biocompatible inertness, high surface-to-volume ratio, and energy absorbance properties. In this study, carboxylated nanodiamond (ND–COOH) was reduced to hydroxylated nanodiamond (ND–OH) for stable and pH-independent colloidal dispersity. The poorly water-soluble paclitaxel (PTX) was physically loaded into ND–OH clusters, forming amorphous PTX nanostructure on the interparticle nanocage of the ND substrate. Stable physical PTX loading onto the ND substrate with stable colloidal stability showed enhanced PTX release. ND–OH/PTX complexes retained the sustained release of PTX by up to 97.32% at 70 h, compared with the 47.33% release of bare crystalline PTX. Enhanced PTX release from ND substrate showed low cell viability in Hela, MCF-9, and A549 cancer cells due to sustained release and stable dispersity in a biological aqueous environment. Especially, the IC₅₀ values of ND–OH/PTX complexes and PTX in Hela cells were 0.037 μg/mL and 0.137 μg/mL, respectively. Well-dispersed cellular uptake of suprastructure ND–OH/PTX nanocomplexes was directly observed from the TEM images. ND–OH/PTX nanocomplexes assimilated into cells might provide convective diffusion with high PTX concentration, inducing initial necrosis. This study suggests that poorly water-soluble drugs can be formulated into a suprastructure with ND and acts as a highly concentrated drug reservoir directly within a cell

Effects of HAT-CN Layer Thickness on Molecular Orientation and Energy-Level Alignment with ZnPc

Efficient energy-level alignment is crucial for achieving high performance in organic electronic devices. Because the electronic structure of an organic semiconductor is significantly influenced by its molecular orientation, comprehensively understanding the molecular orientation and electronic structure of the organic layer is essential. In this study, we investigated the interface between a 1,4,5,8,9,11-hexaazatriphenylene hexacarbonitrile (HAT-CN) hole injection layer and a zinc-phthalocyanine (ZnPc) p-type organic semiconductor. To determine the energy-level alignment and molecular orientation, we conducted in situ ultraviolet and X-ray photoelectron spectroscopies, as well as angle-resolved X-ray absorption spectroscopy. We found that the HAT-CN molecules were oriented relatively face-on (40°) in the thin (5 nm) layer, whereas they were oriented relatively edge-on (62°) in the thick (100 nm) layer. By contrast, ZnPc orientation was not significantly altered by the underlying HAT-CN orientation. The highest occupied molecular orbital (HOMO) level of ZnPc was closer to the Fermi level on the 100 nm thick HAT-CN layer than on the 5 nm thick HAT-CN layer because of the higher work function. Consequently, a considerably low energy gap between the lowest unoccupied molecular orbital level of HAT-CN and the HOMO level of ZnPc was formed in the 100 nm thick HAT-CN case. This may improve the hole injection ability of the anode system, which can be utilized in various electronic devices

Ordered assemblies of Fe3O4 and a donor-acceptor-type pi-conjugated polymer in nanoparticles for enhanced photoacoustic and magnetic effects

We report that the ordered structure in the assemblies of iron oxide nanoparticles in conjugated polymer nanoparticles is the key to achieve better properties to realize multimodal theranostic agents for magnetic resonance and photoacoustic imaging. Hybrid nanoparticles of a conjugated polymer (PCPDTBT), a phospholipid (D8PE) with a primary amine polar head, and iron oxide (Fe3O4) nanoparticles were prepared by a phase-separated film shattering process by varying the iron oxide concentration while maintaining a fixed mixing ratio of PCPDTBT and D8PE. Notably, the hybrid nanoparticles assembled at a molar mixing ratio of 1:1:0.8 (PCPDTBT/D8PE/Fe3O4) exhibited the shortest transversal relaxation time, T-2, and a photoacoustic signal 22 times higher than that obtained at the 1:1:0 mixing ratio. Structural analysis by X-ray diffraction together with the measurements of energy transfer by transient absorption spectroscopy confirmed that the structural ordering of these hybrid nanoparticles was responsible for their enhanced photoacoustic and magnetic properties

Energy-Absorbing and Local Plasmonic Nanodiamond/Gold Nanocomposites for Sustained and Enhanced Photoacoustic Imaging

Photoacoustic (PA) imaging is a laser-mediated optical ultrasound-based visualization that allows imaging of optical energy absorbers in deep tissue, offering higher spatial resolution, compared with that of NIR fluorescence. To enhance a gold nanoparticles-based PA agent, carbon crystalline nanodiamonds and gold nanocomposites (NDAuNPs) were synthesized by chemical reduction of a carboxylate nanodiamond and gold precursor. Reduced hydroxyl-terminated nanodiamonds have stable colloidal dispersion and provide a platform where AuNPs are localized on the ND surface with high density. NDAuNP agglutinates were 100 nm in size, and AuNPs with a size distribution of 5–20 nm were chemically conjugated on the ND surface. The surface-enhanced Raman scattering spectra showed enhanced intensity of NDAuNPs in a concentration-dependent manner. Energy-absorbing nanodiamonds facilitated energy transfer into AuNPs, inducing a local plasmonic effect. The PA signal of NDAuNPs was stronger than that of the AuNPs, as well as the signal maintenance during a prolonged period of laser irradiation. Tissue images of TEM showed that after 2 h irradiation NDAuNPs were maintained without gold degradation, while AuNPs were degraded. The local plasmonic and the energy-absorbing properties of NDAuNPs amplified the PA signal and impeded the degradation of gold without PA signal decay. The NDAuNP nanocomposites may serve as an imaging probe, providing high PA amplitudes

Transcriptional Regulation by ATOH1 and its Target SPDEF in the IntestineSummary

Background & Aims: The transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown. Here, we aimed to identify ATOH1 targets and to identify transcription factors that are likely to co-regulate gene expression with ATOH1. Methods: We used a combination of chromatin immunoprecipitation and messenger RNAâbased high-throughput sequencing (ChIP-seq and RNA-seq), together with cell sorting and transgenic mice, to identify direct targets of ATOH1, and establish the epistatic relationship between ATOH1 and SPDEF. Results: By using unbiased genome-wide approaches, we identified more than 700 genes as ATOH1 transcriptional targets in adult small intestine and colon. Ontology analysis indicated that ATOH1 directly regulates genes involved in specification and function of secretory cells. De novo motif analysis of ATOH1 targets identified SPDEF as a putative transcriptional co-regulator of ATOH1. Functional epistasis experiments in transgenic mice show that SPDEF amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes. Conclusions: This study unveils the direct targets of ATOH1 in the adult intestines and illuminates the transcriptional events that initiate the specification and function of intestinal secretory lineages. Keywords: ATOH1, SPDEF, Transcription, Intestinal Epithelium, Villin-creER, TRE-Spdef, Atoh1GFP, Atoh1Fla